Hypothesis: We recently found that ischemia induces the de novo expression of RAE 1. on renal tubules and the renal expression of NKG2D, the leukocyte receptor for RAE 1. We propose that the expression of RAE 1 allows injured renal epithelia to be recognized by leukocytes via NKG2D. This recognition activates the leukocytes and exacerbates injury. In addition, this recognition may initiate a "RAE 1- NKG2D vicious cycle" of epithelial injury -> RAE 1 expression -> NKG2D leukocyte activation -> epithelial injury -> RAE 1 expression, etc. This may contribute to the progressive nature of renal failure. The overall goal of this R21 (RFA pilot and feasibility program related to the kidney, PA-01-127) is to test the above hypothesis. Although our proposal is currently focused on ischemic acute renal failure, expression of RAE 1 may also occur in other types of renal injury, including progressive renal failure in diabetes mellitus and hypertension, and contribute to perpetuating the injury in those diseases. Specific Aim I: Progressive renal insufficiency develops over 20 weeks after severe renal ischemia in published models; when during this period are RAE1 and NKG2D expressed? Specific Aim II: Determine which NKG2D-expressing leukocyte(s) contribute to renal injury after ischemia. Such leukocytes may include NK cells, NK T cells, macrophages, CD8 T cells, and/or T cells. Determine if progressive renal failure is prevented by eliminating specific populations of these leukocytes using transgenic knockout mice, and monoclonal antibodies. Specific Aim III: Examine the regulation of RAE 1 expression on renal tubule cells in vitro and in vivo. The "RAE 1 - NKG2D vicious cycle" proposed here would be a novel insight into progressive renal injury. New therapy might be directed at interdicting this vicious cycle.